Curcumin and tetrahydrocurcumin derivatives

ABSTRACT

The invention relates to novel curcumin and tetrahydrocurcumin derivatives, which have been modified at one phenolic group to incorporate more-reactive groups. The curcumin and tetrahydrocurcumin derivatives are in the form of monomers, dimmers, and polymers.
 
Z-L n -Y  (I)
 
wherein: Z is represented by:

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.12/445,356, filed on Jun. 7, 2010, which is the national stage of PCTApplication No. PCT/US2007/021805, filed on Oct. 12, 2007, which in turnclaims the benefit of U.S. Provisional Application No. 60/829,185, filedOct. 12, 2006, all of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Curcuma longa commonly referred to as turmeric is used in south Asiancooking, as a cosmetic, and in the ancient Ayurvedic system of medicine.The Banerjee lab at College of Staten Island and other groups haveestablished that curcumin(1Z,6Z)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene 3,5-dione, theprimary active ingredient in turmeric, has potent anticancer properties.Curcumin exerts its anticancer effect through the suppression of NF-kβ.Curcumin mediates its therapeutic effect by regulating the transcriptionfactor NF-kβ and NF-kβ regulated gene products COX-2, cyclin D1,adhesion molecules, MMPs, inducible nitric oxide synthase, Bcl-XL, Bcl-2and TNF.

Curcumin has two phenolic groups, which can be used for chemicalmodification. Most curcumin derivatives reported in literature aresymmetric in that both the phenolic groups have been chemically modifiedin the same way. Rare exceptions have been reported. For example, theMizushina, et al. reference [5] reported the use of monoacetylcurcuminas an inhibitor of eukaryotic DNA polymerase λ and as a ligand forinhibitor-affinity chromatography. See Mizushina, et al.Monoacetylcurcumin: A new inhibitor of eukaryotic DNA polymerase and anew ligand for inhibitor-affinity chromatography, Biochemical andBiophysical Research Communications (2005) 337, 1288-1295. The utilityof monoacetylcurcumin is limited since it does not contain a reactivegroup at the phenolic position.

One of the major limitations of unmodified curcumin is its poor waterand plasma solubility. A recent study has shown that even doses as highas 8 g of curcumin per day administered to human subjects result in anaverage peak serum concentration of only 652.5 ng/ml [9]. There is aneed for curcumin derivatives that have improved water solubility andthat still maintain their biological activity. For example, unmodifiedphenolic groups, in many cases, are responsible for beneficialantioxidant properties.

U.S. Pat. No. 5,861,415 describes a bioprotectant composition containingcurcuminoids, their method of use and extraction processes for obtainingthem. Curcuminoids were found to have anti-oxidant, anti-inflammatory,antibacterial, antifungal, ant parasitic, antimutagen, anticancer, anddetox properties. U.S. Pat. No. 5,891,924 describes a method ofinhibiting the activation of NF kappa B transcription factor usingcurcumin. U.S. Pat. No. 6,653,327 describes a cross-regulin compositionof tumeric derived tetrahydrocurcumin (THC) for skin lightening andprotection against UVB rays. U.S. Pat. No. 6,887,898 describes tumericextracts to be effective in treating beta-Amyloid protein-induceddisease.

SUMMARY OF THE INVENTION

In one embodiment, the invention related to a curcumin derivative havingthe formula I:Z-L_(n)-Y   (I)wherein:Z is represented by:

-   A is −CH₂—CH₂— or —CH═CH—;-   L is —[C(O)]_(n1)—R¹—;-   n is 0 or 1;-   n1 is 0 or 1;-   R¹ is R², R^(3a), R⁴, or R⁵;-   R² is a saturated or unsaturated, branched or unbranched hydrocarbyl    with 1 to 18 carbon atoms;-   R^(3a) is —(CH₂—CH₂—O)_(n2)—;-   R^(3b) is —(O—CH₂—CH₂)_(n2)—;-   n2 is an integer between 1 and 2,000;-   R⁴ is —R²—R^(3a)—, —R²—R^(3b)—, or —R^(3a)—R²—;-   R⁵ is —R⁹—R⁶—R⁹—;-   R⁶ is —C(O)—NH—R^(3a)—;-   Y is —CH═CH—C(O)OR⁸, —CH═C(CH₃)—C(O)OR⁸, —COOR⁷, —N₃, —C≡C—R⁸, —NH₂,    —CHO, —OH, -epoxide-R⁸, —SH, or -maleimide;-   with the proviso that when L is 0, Y is —CH═CH—C(O)OR⁸ or    —CH═C(CH₃)—C(O)OR⁸;-   with the proviso that when R¹ is R^(3a) or —R²—R^(3a)—, Y is    —CH═CH—C(O)OR⁸ or —CH═C(CH₃)—C(O)OR⁸;-   R⁷ is hydrogen, C₁₋₄ alkyl, or a moiety such that —COOR⁷ is an    activated ester;-   R⁸ is hydrogen or C₁₋₄ alkyl; and-   R⁹ is independently C₁₋₄ alkyl.

In another embodiment, the invention relates to a curcumin dimer havingthe formula II:Z^(a)-L^(a)-Y^(a)-(L^(b))_(n3)-Y^(b)-L^(c)-Z^(b)   (II)wherein:Z^(a) and Z^(b) are represented by

-   A is independently —CH₂—CH₂— or —CH═CH—;-   L^(a), L^(b), and L^(c) are independently —[C(O)]_(n1)—R^(1a)—;-   n1 is independently 0 or 1;-   R^(1a) is independently R², R^(4a) or R⁵;-   R² is independently a saturated or unsaturated, branched or    unbranched hydrocarbyl with 1 to 18 carbon atoms;-   R^(3a) is —(CH₂—CH₂—O)_(n2)—;-   R^(3b) is —(O—CH₂—CH₂)_(n2)—;-   n2 is independently an integer between 1 and 2,000;-   R^(4a) is —R²—R^(3b)— or —R^(3a)—R²—;-   R⁵ is —R⁹—R⁶—R⁹—;-   R⁶ is —C(O)—NH—R^(3a)—;-   Y^(a) and Y^(b) are independently —COOR⁹—, -triazolyl-, —NH—, —O—,    or —S—S—;-   R⁹ is C₁₋₄ alkyl;-   n3 is independently 0 or 1;-   when n3 is 0, Y^(a) and Y^(b) are modified so that at least one    covalent bond is formed between Y^(a) and Y^(b), and-   when n3 is 1, L^(b) is modified so that at least one covalent bond    is formed between L^(b) and both Y^(a) and Y^(b).

DETAILED DESCRIPTION

The invention relates to novel curcumin derivatives in which one of thephenolic groups has been modified.

In one aspect of the invention, the curcumin derivative is representedby formula I, i.e., Z-L_(n)-Y. In formula I, Z represents:

A represents —CH₂—CH₂— or —CH═CH—. When A is —CH₂—CH₂—, Z-L_(n)-Y is atetrahydrocurcumin derivative. When A is —CH═CH—, Z-L_(n)-Y is acurcumin derivative.

L is a linker represented by —[C(O)]_(n1)—R¹—. The letter n is 0 or 1.When n is 0, there is no linker. The letter n1 is 0 or 1. For example,when n1 is 1, L is

When n1 is 0, then L is —R¹—.

R¹ is represented by R², R^(3a), R⁴, or R⁵. R² is a hydrocarbyl chainwith 1 to 18 carbon atoms. Hydrocarbyl chains are saturated orunsaturated, and branched or unbranched. The carbon atoms of a chain canall be saturated, or can all be unsaturated. Alternatively, the chaincan comprise a mixture of saturated and unsaturated carbon atoms. Theunsaturated hydrocarbyl chains contain one or more double and/or triplebonds.

Some examples of suitable, saturated straight-chained hydrocarbyl chainsinclude methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, dodecyl,hexadecyl, and octadecyl chains. Preferred straight chain alkyl groupsinclude methyl and ethyl. Some examples of suitable, unsaturatedstraight-chained hydrocarbyl chains include 3-butenyl, 1,3-heptadienyl,2-dodecynyl, oleyl, linoleyl, and linolenyl chains.

Some examples of suitable saturated, branched alkyl groups includeiso-propyl, iso-butyl, sec-butyl, t-butyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl (isopentyl), 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl (neopentyl), 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl groups, and 2-methyl, 5-ethyldecyl.Preferred branched alkyl groups include isopropyl and t-butyl. Somesuitable examples of unsaturated, branched alkyl groups include1-methyl-4-pentenyl and 7-ethyl-10,15-hexadecadienyl.

R^(3a) is represented by —(CH₂—CH₂—O)_(n2)—, and R^(3b) is—(O—CH₂—CH₂)_(n2)—. R^(3a) and R^(3b) represent polyethylene glycolchains. The variable n2 is an integer with a minimum value of one, two,or three. The maximum value of n2 is four, twelve, fifty, or 2,000.Preferably, the maximum value of n2 is fifty, and more preferablytwelve. For example, if n2 is ten, then R^(3a) is a polyethylene glycolpolymer with ten ethylene glycol units.

The variable R⁴ is represented by —R²—R^(3a)—, —R²—R^(3b)—, or—R^(3a)—R²—. For example, when R⁴ is —R²—R^(3a)—; R² is an ethylenechain, and n2 is five, then R⁴ is —CH₂—CH₂—(CH₂—CH₂—O)₅—. Similarly,when R⁴ is —R²—R^(3b)—; R² is a methylene chain; and n2 is 8, then R⁴ is—CH₂—(O—CH₂—CH₂)₈—.

R⁵ is represented by —R⁹—R⁶—R⁹—, and R⁶ is represented by—C(O)—NH—R^(3a)—. R⁹ is independently represented by C₁₋₄ alkyl.

C₁₋₄ alkyl represents a branched or unbranched, saturated or unsaturatedcarbon chain with a minimum of one carbon atom. The maximum number ofcarbon atoms is four. Preferably, the C₁₋₄ alkyl is a methylene orethylene chain.

When R¹ is R⁵, R⁹ is independently a methylene or ethylene chain, and n2is ten, then R¹ is represented by:

Y represents a reactive moiety, e.g., functional group. Y is—CH═CH—C(O)OR⁸, —CH═C(CH₃)—C(O)OR⁸, —COOR⁷, —N₃, —C≡C—R⁸, —NH₂, —CHO,—OH, -epoxide-R⁸, —SH, or -maleimide. When R¹ is R^(3a) or —R²—R^(3a)—,Y is either —CH═CH—C(O)OR⁸ or —CH═C(CH₃)—C(O)OR⁸.

The variable R⁷ is hydrogen, C₁₋₄ alkyl, or a moiety such that —COOR⁷ isan activated ester. R⁸ is hydrogen or C₁₋₄ alkyl.

Activated esters are esters which spontaneously react with an aminogroup. Common activated esters include nitrophenyl, pentafluorophenyland succinimido esters. Nitrophenyl esters can be substituted at anyposition with one, tow, or three nitro groups, e.g., 2, 3, or 4 nitro,3, 5 dinitro, or 2, 4, 6 trinitro. Preferably, the activated ester is anN-hydroxysuccinimide ester or a nitrophenyl ester. Compound 1d in Scheme1 below contains an activated ester.

In another aspect of the invention, the curcumin derivatives are dimersrepresented by formula II, i.e.,Z^(a)-L^(a)-Y^(a)-(L^(b))_(n3)-Y^(b)-L^(c)-Z^(b). In formula I, Z^(a)and Z^(b) are represented by:

A, n1, n2, R², R^(3a), R^(3b), R⁵, R⁶, and R⁹ are as described above.

L^(a), L^(b), and L^(c) are independently —[C(O)]_(n1)—R^(1a)—. R^(1a)is independently R², R⁴, or R⁵.

Y^(a) and Y^(b) are independently —COOR⁹—, -triazolyl-, —NH—, —O—, or—S—S—. For example, Y^(a) may represent —O— and Y^(b) may represent-triazolyl-.

R^(4a) is represented by —R²—R^(3b)— or —R^(1a)—R²—.

The variable n3 is independently 0 or 1. When n3 is 0, Y^(a) and Y^(b)are modified so that at least one covalent bond is formed between Y^(a)and Y^(b), and when n3 is 1, L^(b) is modified so that at least onecovalent bond is formed between L^(b) and both Y^(a) and Y^(b).

Covalent bonds can be formed at any available atom on the triazolylgroup.

In the present invention, various parameters are defined (e.g. A, L, Y,n1, n2, R¹, R², R³, R⁴). Within each parameter, more than one element(e.g. number, chemical moieties) are listed. It is to be understood thatthe instant invention contemplates embodiments in which each elementlisted under one parameter, may be combined with each and every elementlisted under any other parameter. For example, A is identified above asrepresenting —CH₂—CH₂— or —CH═CH—. Y is identified above as being—CH═CH—C(O)OR⁸, —CH═C(CH₃)—C(O)OR⁸, —COOR⁷, —N₃, —C≡C—R⁸, —NH₂, —CHO,—OH, -epoxide-R⁸, —SH, or -maleimide. Each element of A (—CH₂—CH₂— or—CH═CH—) can be combined with each and every element of Y(—CH═CH—C(O)OR⁸, —CH═C(CH₃)—C(O)OR⁸, —COOR⁷, —N₃, —C≡C—R⁸, —NH₂, —CHO,—OH, -epoxide-R⁸, —SH, or -maleimide). For example, in one embodiment, Amay be —CH₂—CH₂— and Y may be —N₃. Alternatively, A may be —CH═CH— and Ymay be -epoxide-R⁸, etc. Similarly, a third parameter is n1, in whichthe elements are defined as 0 or 1. Each of the above embodiments may becombined with each and every element of n1. For example, in theembodiment wherein A is —CH₂—CH₂— and Y is —COOR⁷, n1 may be 1 (or anyother number within the elements of n1).

In more specific embodiments, the invention relates to six curcuminmonomers with the following modification at the phenolic group: a singleacrylate or methacrylate, a single carboxylic acid, alkyne,N-Hydroxysuccinimide, a single azide group andCurcumin/tetrahydrocurcumin-triazole PEG, compounds 1a, 1b, 1c, 1d, 1e,and 1f, respectively, of Scheme 1.

In scheme 1.1, method for synthesizing the compounds of Scheme 1 areshown. The mono-carboxylic acid derivative of curcumin 1b is synthesizedby reacting curcumin 1 with glutaric anhydride in the presence of base.Curcumin mono-azide derivative 1e is synthesized by an amide couplingreaction between curcumin mono-carboxylic acid 1b and an Amino-PEG Azideusing 1,3-dicyclohexylcarbodiimide (DCC) at room temperature. Themono-alkyne derivative of curcumin 1c is synthesized by etherifyingcurcumin with propargyl bromide; K₂CO₃ is used as a base in DMF at roomtemperature. Etherification involving curcumin and propargyl bromideproceeded efficiently at room temperature. Mono-triazole-PEG derivativeof curcumin 1f is synthesized by condensing mono-alkyne derivative ofcurcumin 1c with azidotrietheylene glycol under the Sharpless “click”condition (copper(II) sulfate and sodium ascorbate). A curcumin dimer issynthesized by reacting curcumin mono-alkyne derivative 1c with curcuminmono-azide derivative 1e using copper(II) sulfate and sodium ascorbate.The curcumin dimer, 1 g has two curcumin moieties connected by atriazole link and a PEG spacer. The dimer has two phenolic groups likethe parent molecule 1.

The carboxylic acid group of 1b can be conjugated to proteins,biopolymers and synthetic polymers; the azide 1e and the alkynederivative 1c can be attached to modified proteins and polymers via the“click” bioconjugation reaction.

In another embodiment, bioconjugates can be synthesized using thecurcumin derivatives of the invention. The reactive curcuminintermediate derivatives react with a variety of biopolymers to formmacromolecular entities that can be useful in delivering the curcuminentities in vivo in a biocompatible and efficacious manner that enhancesbioactivity.

For example, the curcumin intermediate derivatives can be reacted withpolysaccaride containing pendant amines. This involves reaction of acarboxyl acid containing curcumin derivative with a polysaccaridecontaining pendant amine such as amino dextran shown in Scheme 4. SeeHermanson, G. T. Bioconjugate Techniques; Academic Press: San Diego,Calif., 1996; Chapter 15, P 624. The portion of the Hermanson describingthe synthesis of amino dextrans is herein incorporated by reference.

In another example, the curcumin intermediate derivatives can be reactedwith proteins having amine residues, e.g., lysine. An example of this isgiven in Scheme 5. Note that a protein such as avidin containing lysinegroups can react with a carboxyl modified curcumin to produce abioconjugate with an amine linkage. A protein with lysine residues whichis reacted with a carboxyl containing molecule is described in Raja, etal. “One-Pot Synthesis, Purification, and Formulation ofBionanoparticle-CpG Oligodeoxynucleotide Hepatitis B Surface AntigenConjugate Vaccine via Tangential Flow Filtration.” Bioconjugate Chem.,2007, 18, 285. The portion of the Raja, et al. reference describingLysine modification of proteins is incorporated herein by reference.Other possible synthesis shown in Scheme 5 include either acetylenemodified curcumin reacted with an azide modified protein or azidemodified curcumin reacted with an acetylene modified protein, to aproduce a curcumin protein bioconjugate having a triazole linkage.

Synthetic polymers can also be reacted with curcumin intermediatederivatives to form a synthetic polymer conjugate. For example, an aminependant synthetic polymer such as poly 2 amino ethyl methacrylate can bereacted with a carboxyl containing curcumin derivative to produce asynthetic polymer conjugate with pendant curcumin moieties connected tothe polymer using amide linkages. This can be found in Scheme 3. Inanother example, a carboxylic pendant synthetic polymer such as polyacrylic acid can be reacted with a amine containing curcumin derivativeto produce a synthetic polymer conjugate with pendant curcumin moietiesconnected to the polymer using amide linkages.

Another class of synthetic polymer conjugates would contain polyethyleneglycol (PEG). PEG containing polymers are typically water soluble andbiocompatible. For example an azide terminated synthetic polymer such asPEG azide can be reacted with an alkyne containing curcumin derivativeto produce a synthetic polymer conjugate with curcumin moietiesconnected to the polymer using triazole linkages 1f.

Similarly, the monomers can be polymerized to form curcumin polymers andcopolymers. In Scheme 2, polymers and copolymers are produced bypolymerizing curcumin/tetrahydrocurcumin acrylate and methacrylate byuncontrolled and controlled radical polymerization methods, e.g., atomtransfer radical polymerization or RAFT.

Synthetic polymers such as poly-2-aminoethyl methacrylate, polylysine,and dendrimers can be covalently modified with multiple aminefunctionalities. Polymers displaying multiple copies of azides oralkynes are shown in Scheme 3. Biopolymers including polysaccharidessuch as dextrans using the curcumin analogs 1a-1e are shown in Scheme 4.The chemical modification of proteins such as Protein A, Protein G,Protein L, antibodies, avidin, TAT peptide, collagen, elastin andbionanoparticles using the analogs 1a-1e and the resulting curcuminmodified polymers are shown in Scheme 5. In another embodiment, theprotein is streptavidin.

Curcumin/THC and the THC and Curcumin derivatives of the invention areused as monomers in step condensation polymerization to produce bothhomopolymers and copolymers with comonomers, e.g., lactic acid, glycolicacids and amino acids, as well as any of the polymers mentioned above.

Polymers of lactic acid and glycolic acid have been reported inliterature for biomedical applications.^(25,13) Curcumin-modifieddextrans are a typical example of curcumin modified polymerssynthesized: Aminated dextrans were conjugated with Curcumin-R—COOH (1b)(Scheme 4). The resulting conjugates were characterized via sizeexclusion FPLC. The dextran curcumin conjugates elute at the sameretention time as the starting amino dextran and has absorbance maximumat 430 nm, which arises from the conjugated curcumin.

Novel Curcumin/tetrahydrocurcumin dimers synthesized by connecting twocurcumin molecules using spacers such as polyethylene glycol or acarbohydrate, the covalent connecting links betweencurcumin/tetrahydrocurcumin or its derivatives 1a-1e and the spacersbeing an ester, amide or triazole are claimed (Scheme 6), the dimer havetwo phenolic groups like the parent molecule along with improved watersolubility and amplified biological activity.

Uses for Curcumin DerivativesBioconjugation Dyes and Imaging

Small molecule and polymeric curcumin derivatives were studied for useas bioconjugation dyes and for imaging applications with specialemphasis on imaging amyloid plaque, in vitro and in vivo.

Curcumin has absorbance maximum at 430 nm and a molar extinctioncoefficient of 50,000; unlike many other dyes curcumin is completelynon-toxic. Curcumin dyes can be excited at 460 nm to produce strongfluorescence emission. The same optics and technology (for techniqueslike confocal microscopy, fluorescence microcopy and gel imaging) whichhave been widely established and commercialized for the chromophorefluorescein can be employed for curcumin conjugates.

Inexpensive, eco-friendly dyes based on this ‘green fluorescentchemical’ for bioconjugation applications can be made where thebiopolymer component is either a polysaccharide, a protein, DNA or RNA.Curcumin-R—COOH (1b) has been modified to produce the correspondingN-hydroxy succinimide (1d), curcumin-alkyne (1c) and curcumin azide(1e).

Each curcumin derivative is bioconjugated to create a biopolymer thatcan be used as an eco-friendly dye. For example, compounds 1b and 1d canbe conveniently conjugated to the lysine residues of proteins, the azideand the alkyne derivatives can be attached to proteins via the ‘click’bioconjugation reaction [6,7]. Compounds 1c and 1e have the advantagethat unlike most reactive groups which are used for bioconjugation,alkyne and azide groups are stable in aqueous media (Scheme 5). Theabsorbance and fluorescence properties of these dyes are similar to theparent molecule. The molar extinction coefficient of some dyes arepresented in Table 1.

TABLE 1 Molar Extinction Coeffecient of Curcumin Analogs MolarExtinction Molecule Coeffecient Curcumin- 57022 Carbxylic Acid Curcumin-26764 Azide Curcumin- 29510 Alkyne Curcumin 46874 AcrylateAlzheimer's and Prion Disease

Alzheimer's disease (AD) involves amyloid β accumulation, inflammationand oxidative damage of the brain. It has recently been shown usingtransgenic mouse model studies that injected curcumin crosses theblood-brain barrier and binds amyloid plaques. When fed to the mice withadvanced amyloid accumulation, curcumin labeled the plaques and reducedamyloid levels and plaque burden [8].

The curcumin analogs in Scheme 1 were analyzed for their ability tolabel amyloid plaque. The results were good. Curcumin-dextran (50 nmolwith respect to curcumin) was used to efficiently label human hearttissue (tissue slides were purchased from Sigma), the stained slideswere imaged by confocal laser scanning microscopy.

The curcumin chromophore was excited with a 458 nm laser. Opticsemployed for the fluorescein chromophore will work efficiently for thecurcumin derivatives of the claimed invention.

The superior solubility and polyvalent presentation of multiple copiesof curcumin on polymeric scaffolds presented in Schemes 2-6 will enablemore efficient labeling and dissolution of amyloid in vitro and in vivo.The curcumin modified polymers will have enhanced pharmacokinetics viaincreased plasma circulation time compared to small molecule analogs[10]. Many of the conjugates such as the TAT peptide-curcumin conjugatewould cross the blood brain barrier effectively because it has beenpreviously shown that TAT peptide helps in transporting quantum dotseffectively across the blood brain barrier [11]. The curcumin dimersdisclosed in this patent have two phenolic groups per molecule alongwith superior water and plasma solubility compared to the parentcurcumin molecule.

Congo red is the current dye of choice to stain amyloid tissue [12].However, Congo red has the disadvantage of being toxic. A much highercongo red dye concentration must be used for staining compared to theconcentration of curcumin. Curcumin dyes have the advantage of beingnon-toxic.

Polarized light micrograph images of heart amyloid fibrils stained usingdextran-curcumin conjugate and control Congo red stained sample provethat the curcumin analogs of the invention are excellent stainingreagents. Small molecule analogs and curcumin modified polymers can beused for both diagnostic and therapeutic applications in vitro and invivo in diseases associated with amyloid accumulation and uncontrolledprotein aggregation including Alzheimer's and Mad Cows disease (priondisease) in mammals including homo sapiens.

For example, the ability of Curcumin-COOH (1b) to dissolve amyloidplaque can be seen. Amyloid plaque (Fibrils) were formed by adding 40 μLof the amyloidβ peptide Aβ-40 solution to a 96 well plate (40 μL perplate) and incubated for 3 days at 37° C. Either Curcumin-COOH orcontrol buffer was added to the wells. The final concentrations were 8μM Curcumin-COOH and 50 μG/mL Aβ-40. The Curcumin-COOH and controlamyloid plaque samples were incubated for three more days at 37° C. Theformation of plaque in the control samples was inferred from the UVspectrum of the control sample. Increased absorbance intensitythroughout the UV-visible spectrum due to light scattering from theaggregates was observed. The UV spectrum of the Curcumin-COOH treatedamyloid has a reduced absorbance relative to the control samples,aggregates are absent because the curcumin analog dissolves the plaque.The absorbance spectrum results were confirmed by studying the samesamples used for the UV absorbance spectroscopy by Transmission electronmicroscopy. A network of fibers was observed in the control amyloidplaque samples whereas the fibrils were completely absent in the plaquesamples treated with curcumin-COOH. This proves that the curcuminanalogs covered in this patent are very effective in dissolving amyloidplaque.

Curcumin Analogs and Polymer Modified Curcumin Derivatives as AnticancerAgents

The small molecule curcumin analogs including curcumin dimers, curcuminpolymers and curcumin modified polymers, typical examples shown inSchemes 1-6 of the present invention can be used for the treatment ofcancer. The curcumin dimers and the polymer curcumin conjugates of theinvention such as dextran-curcumin conjugates are more potent than theunmodified parent molecule curcumin in their ability to destroyOligodendroglioma cells. Oligodendroglioma cells were treated with 50micro molar concentration of curcumin and asymmetric curcumin dimerstained with DAPPI presented. The curcumin dimmer was observed as beingsuperior in inducing apoptosis relative to the parent compound curcumin.Extensive apoptosis characterized by nuclear condensation (marked bybright blue DAPI staining) is observed in the cells exposed to curcumindimer.

Data obtained at concentrations 20 μM and 50 μM show that the analogscause considerable apoptosis. Very limited cell death is seen in humanfibroblasts, which serve as a benign control cell line. The percentageof apoptosis is lower at higher concentrations (100 μM and more) ascompared to that at 20 μM and 50 μM for all the compounds includingcurcumin because at higher concentration curcumin and analogs of theinvention cause HOG cell necrosis. This alternate pathway of cellkilling has been established via DNA laddering studies.

The blood vessels in tumors have abnormal architectures and impairedfunctional regulation. In particular vascular permeability in tumors isgreatly enhanced for polymers which are retained in tumors for extendedperiods. This phenomenon is referred to as the “enhanced permeabilityand retention (EPR) effect.” Macromolecules are therefore ideal forselective delivery to tumors. The EPR effect has facilitated thedevelopment of macromolecular drugs consisting of various polymer-drugconjugates (pendant type), polymeric micelles, and liposomes thatexhibit better therapeutic efficacy and fewer side effects than theparent low-mol.-wt. compounds [15].

Dextran is non-toxic, it is a naturally occurring polysaccharide that issynthesized in yeast and bacteria. It has been used as a drug carrier totransport greater concentration of anti-neoplastic pharmaceuticals totumor sites in vivo [16] and in synthesizing fluorescent tracers [17].Curcumin-dextran conjugates have multiple copies of curcumin attached todextran. These conjugated have been shown to have an amplifiedefficiency (a polyvalent response) in destroying cancer cells. Thedextran-curcumin conjugates are also highly soluble in water and havethe advantage of enhanced permeation and retention.

Cosmetic Applications

Curcumin is a powerful antioxidant [18] and skin protectant that hasbeen used in oil-based cosmetic formulations in India. For example,curcumin is used in Sparsh™ and Vicco Turmeric Cream™.Tetrahydrocurcumin has been recently used as an additive in cosmeticformulations, because it has skin lightening and antioxidant propertiesand the aesthetic advantage that it is colorless unlike curcumin whichis yellow colored [19, 20,21,22]. Most commercial cosmetic formulationsare not oil-based. Incorporating curcumin or tetrahydrocurcumin intonon-oil-based formulations at high concentrations is challenging becauseboth molecules exhibit poor water solubility.

The novel small molecule and polymeric curcumin/tetrahydrocurcuminderivatives of the invention have improved water solubility and blendingcharacteristics in cosmetic formulations. The polymeric curcuminderivatives have the added advantage that they would be retained for alonger periods on the skin. The polymeric derivatives have severalcopies of tetrahydrocurcumin/curcumin attached per polymer molecule,this polyvalent display of bioactive molecules leads to an amplifiedbiological response of selectively killing cancer cells. The novelcurcumin molecules of the invention may be incorporated into cosmeticformulations for prevention of melanoma by skin damage due to sunlight,for lightening skin color and for protecting the skin from free radicaldamage. Collagen and elastin are routinely used in cosmetic formulationsfor improving the texture of the skin and in anti-aging formulations[23-24]. The novel elastin/collagen conjugates withtetrahydrocurcumin/curcumin of the invention combine the powerful skinprotectant, antioxidant and skin lightening properties of thecurcumin/THC analogs along with the beneficial properties of collagenand elastin in a unique fashion. These compounds represent a newgeneration of active ingredients in cosmetic formulations.

EXAMPLES

The specific examples describe a preferred method for synthesizing thecompounds of the present invention. The scope of this invention is notto be in any way limited by the examples set forth herein.

Reagent-grade solvents such as acetone and tetrahydrofuran were usedwithout further purification. For High Performance Liquid Chromatography(HPLC), methylene chloride was used with Pure Solv™ solvent purificationsystem. Curcumin was obtained from Acros-Organics. Copper acetate andsodium ascorbate were purchased from Sigma. Silica gel 60 F 254 platesfor thin-layer chromatography (TLC) were purchased from Merck. Columnchromatographic separations were carried out using silica gel (Fisher)with a particle size of 0.040-0.063 mm. Nuclear magnetic resonance (NMR)was recorded on Bruker Avance 600 (600 MHz) spectrometers. Mass spectra(ES-MS) were recorded on a LC/MS and Time Of Flight (TOF) massspectrometer. U.V.-Visible spectra were recorded using a ChemStationRev. A.10.01 from Agilent Technologies

Amino Dextran 40, 70, 500 g/mole was purchased from Invitrogen. TheFPLC-AKTA Purifier model 18-1400-00 with the Superose 6 10/300 GL columnfrom Amersham Biosciences was used to analyze pure Amino Dextran 40 k,70 k, and 500 k and the 40 k, 70 k, 500 k and other bio-conjugates.Deionized water was used as the primary solvent which was at a flow rateof 0.200 mL/min. Deionized water was used because Amino Dextran is verysoluble in water, and this would minimize any possible interference withthe absorbance.

Example 1 Synthesis of Mono-Methacryloyl Curcumin 1 and Di-MethacryloylCurcumin 2

One g (2.71 mmol) curcumin was dissolved in 25 ml acetone, 0.37 g (3.66mmol) Et₃N was added dropwise under ice temperature. Methacryloylchloride 0.34 g (3.25 mmol) was added dropwise in 20 ml acetone. Afterthe addition was complete, the reaction mixture was stirred for 95minutes under 0° C. The temperature was then increased to 59° C. andrefluxed overnight under nitrogen. The solution was evaporated underreduced pressure and a sticky solid was obtained. The residue waspurified on column chromatography, eluting with CH₂Cl₂:hexane, 9:1.Yield 1.842 g (19% and 8%). ¹H NMR (CDCl₃), δ (ppm): Compound 1, 2.08(s, 3H); 3.87 (s, 3H); 3.95 (s, 3H); 5.78-5.83 (dd, 2H); 6.38 (s, 1H);6.48-4.57 (dd, 2H); 6.93 (d, 1H); 7.05-7.16 (m, 6H); 7.60-7.62 (d, 2H).¹³C NMR (CDCl₃), δ (ppm): 18.44; 55.93; 101.55; 109.60; 111.45; 114.83;120.98; 121.75; 123.04; 123.31; 124.13; 127.53; 133.96; 135.38; 139.48;141.09; 141.42; 146.78; 147.96; 151.52; 165.24; 181.86; 184.46. MS (ESI)calcd. for C₂₅H₂₄O₇ 436.45. found: 437.2 [M+H]⁺, 459.1 [M⁺+Na]. Compound2, 2.08 (s, 6H); 3.85 (s, 6H); 5.78-5.86 (dd, 4H); 6.38 (s, 2H);6.56-4.59 (d, 2H); 7.09-7.18 (m, 6H); 7.62-7.64 (d, 2H).

Example 2 Synthesis of Mono-Carbonyl Butanoic Acid 3

To a solution of 2.01 g (5.46 mmol) of curcumin, 112 mg (0.92 mmol) ofDMAP, and 0.685 g (6 mmol) glutaric anhydride (95%) in 100 ml THF wasadded 1.33 ml (9.55 mmol) Et₃N. The reaction was stirred at reflux underargon overnight. Purified on column chromatography, eluting withCH₂Cl₂—CH₂Cl₂:MeOH, 95:5. Yield 84%. NMR ¹H (CDCl₃), δ (ppm): compound(3), 1.97-2.14 (m, 2H); 2.43-2.79 (m, 4H); 3.87-3.95 (d, 6H); 5.83 (s,2H); 6.45-6.59 (t, 2H); 6.91-7.18 (m, 6H); 7.57-7.65 (d, 2H). ¹³C NMR(CDCl₃), δ (ppm): 19.98; 32.76; 55.82; 101.61; 109.86; 111.36; 115.04;120.95; 121.54; 123.05; 124.16; 127.35; 133.89; 139.38; 139.99; 141.06;147.03; 148.22; 151.23; 170.98; 177.374; 181.73; 184.65. MS (ESI) calcd.for C₂₆H₂₆O₉: 482.48. found: 483.2 [M+H]⁺.

See Robert E. Gawley; Mykhaylo Dukh; Claudia M. Cardona; Stephan H.Jannach; Denise Greathouse. Org. Lettl., Vol. 7, No. 14, 2005.2953-2956.

Example 3 Synthesis ofMono-2-(2-(2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethylcarbamoylbutanoate-Curcumin 4

To a solution of 158 mg (0.45 mmol) of 3 in 3 mL dry THF at roomtemperature was added 206 mg (0.427 mmol) ofO-(2-Aminoethyl)-O′-(2-azidoethyl)pentaethylene glycol and 96 mg (0.47mmol) of 1,3-dicyclohexylcarbodiimide. The mixture was stirred at 25° C.overnight. The reaction mixture was then diluted with 10 mL of ethylacetate, filtered to remove the urea byproduct, and the organic solventwas removed with a vacuum pump. The product was dissolved in methylenechloride and washed with water. Then, the organic phase was separatedand dried with vacuum pump. The product was purified using columnchromatography, eluting with CH₂Cl₂—CH₂Cl₂:MeOH, 95:5. Yield 29%. NMR ¹H(CDCl₃), δ (ppm): 1.72-1.78 (m, 2H); 2.35-2.38 (m, 2H); 2.66-2.70 (m,2H); 3.37-3.66 (m, 28H); 3.88 (s, 3H); 3.95 (s, 3H); 6.40 (s, 1H);6.48-6.57 (m, 2H); 6.93-6.94 (s, 1H); 7.05-7.27 (m, 6H); 7.59-7.63 (m,2H). MALDI-TOF MS (calcd. for C₄₀H₅₄N₄O₁₄ 814.36). found: 837.38[M⁺+Na], 853.35 [M⁺+K].

See Alwarsamy Jeganathan; Stewart K. Richardson; Rajarathnam S. Mani;Boyd E. Haley; David S. Watt. J. Org. Chem. 1986, 51, 5362-5367.

Example 4 Synthesis of Mono-Propargyl Curcumin 5

Curcumin (5 g, 13.57 mmol) and K₂CO₃ (1.88 g, 13.62 mmol) were dissolvedin 60 mL DMF, and 1.62 g (13.61 mmol) of propargyl bromide was added.The mixture was stirred at room temperature under Ar for 49 h. H₂O wasadded to the mixture and solvent was removed under vacuum. The productwas purified on column chromatography, eluting with CH₂Cl₂: hexane50:50—CH₂Cl₂. Yield 47%. NMR ¹H (CDCl₃), δ (ppm): 2.54 (s, 1H); 3.94 (d,6H); 4.81 (d, 2H); 5.82 (s, 1H); 5.93 (s, 1H); 6.47-6.52 (t, 2H);6.93-7.15 (m, 6H); 7.59-7.61 (dd, 2H). MS (ESI) calcd. for C₂₄H₂₂O₆:406.43. found: 407.2 [M+H]⁺, 445.2 [M⁺+K].

Example 5 Synthesis ofMono-2-(2-(2-(4-(methylene)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethanol-curcumin6

To a stirred solution of Mono-Propargyl Curcumin 5 (63 mg, 0.16 mmol)and 2-(2-(2-azidoethoxy)ethoxy)ethanol (46 mg, 0.26 mmol) in ^(t)BuOH(1.1 mL) and CHCl₃ (0.3 mL) was added a prepared solution of Cu(OAc)₂ (8mg, 0.03 mmol) and sodium ascorbate (13 mg, 0.07 mmol) in H₂O (1.3 mL).After vigorous stirring overnight the solvent was removed under vacuum.The mixture was dissolved in CHCl₃, washed with H₂O and the organicphase was separated, dried over Na₂SO₄ and evaporated. Purification wasperformed by column chromatography, eluting with CH₂Cl₂—CH₂Cl₂: MeOH98:2. Yield 26%. NMR ¹H (CDCl₃), δ (ppm): 3.55-3.60 (m, 8H); 3.72-3.72(t, 3H); 3.87-3.94 (m, 8H); 4.54-4.55 (t, 2H); 5.80 (s, 1H); 6.07 (s,1H); 6.46-6.50 (dd, 2H); 6.92-6.94 (d, 1H); 7.05-7.12 (m, 5H); 7.56-7.60(q, 2H); 7.92 (s, 1H).). MS (ESI) calcd. for C₃₀H₃₅N₃O₉: 581.61. found:582.3 [M+H]⁺, 604.3 [M⁺+Na], 620.3 [M⁺+K].

See Maarten Ijsselstijn and Jean-Christophe Cintrat. Tetrahedron. 2006,62, 3837-3842.

Example 6 Synthesis of(2-(2-(2-(2-(2-(2-(2-(4-methylene)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethylcarbamoylbutanoate curcumin dimer 7

Compound 7 was synthesized using the same procedure employed for thesynthesis of 6. The product was isolated in 41% yield. NMR ¹H (CDCl₃), δ(ppm): 1.60-1.63 (bd, 2H); 2.26-2.29 (t, 2H); 2.47-2.49 (t, 2H);3.41-3.42 (t, 2H); 3.53-3.63 (m, 26H); 3.86-3.95 (m, 12H); 4.54-4.55 (d,4H); 5.33 (s, 2H); 6.55-6.56 (bd, 4H); 6.94-7.11 (bm, 12H); 7.59 (s,4H); 7.87 (s, 1H).). MALDI-TOF MS (calcd. for C₆₄H₇₆N₄O₂₀ 1220.51).found: 1243.52 [M⁺+Na], 1259.47 [M⁺+K].

See Maarten Ijsselstijn and Jean-Christophe Cintrat. Tetrahedron. 2006,62, 3837-3842.

Example 7 Synthesis of Dextran 40K Mono-Carbonyl Butanoic Acid CurcuminConjugate 1

Dextran 32 mg (8×10⁻⁴ mmol), mono-carbonyl butanoic acid curcumin 69 mg(1.4×10⁻³ mmol) and DCC (1,3-dicyclohexylcarbodiimide) 48 mg (2.3×10⁻³mmol) were dissolved in 1 ml dry DMSO. The reaction was stirred for 24 hat reflux under argon. The solution was filtered, dialyzed withSnakeSkin pleated dialysis tubing with Millipore water, centrifuged andlyophilized. A cotton candy-like product (31 mg) was obtained inquantitative yield. NMR ¹H (D₂O), δ (ppm): compound 1, 1.77 (m,);1.93-2.04 (bm); 2.17-2.21 (m); 2.86-2.91 (m); 3.52-3.60 (m); 3.72-3.78(m); 3.92-4.01 (dd); 5.00 (d). Number of Curcumin molecules attached perpolymer molecule is 10 (Estimated from UV spectroscopy using theextinction coefficient for Curcumin-COOH).

Example 8 Synthesis of Dextran 70K Mono-Carbonyl Butanoic Acid CurcuminConjugate 2

Dextran 122 mg (3×10⁻³ mmol), Mono-carbonyl butanoic acid curcumin 16 mg(3.3×10⁻⁴ mmol) and DCC (1,3-dicyclohexylcarbodiimide) 10 mg (4.8×10⁴mmol) were dissolved in 5.5 ml dry DMSO. The reaction was stirred for 24h at reflux under argon The solution was filtered, dialyzed withSnakeSkin pleated dialysis tubing with Millipore water, centrifuged andlyophilized. The product resembled cotton candy and the yield wasquantitative. NMR ¹H (D₂O), δ (ppm): compound 2, 1.35-1.39 (m); 1.67(m,); 1.78-1.92 (bm); 2.33 (bm); 2.41-2.44 (t); 3.53-3.56 (t); 3.59-3.61(m); 3.73-3.79 (m); 3.93-4.02 (dd); 5.00 (d). Number of Curcuminmolecules attached per polymer molecule is 22 (Estimated from UVspectroscopy using the extinction coefficient for Curcumin-COOH).

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We claim:
 1. A curcumin derivative having the formula I:Z-L_(n)-Y   (I) wherein: Z is represented by:

A is —CH₂—CH₂— or —CH═CH—; L is —[C(O)]_(n1)—R¹—; n is 0 or 1; n1 is 1;R¹ is R², R^(3a), R⁴, or R⁵; R² is a saturated or unsaturated, branchedor unbranched hydrocarbyl with 1 to 18 carbon atoms; R^(3a) is—(CH₂—CH₂—O)_(n2)—; R^(3b) is —(O—CH₂—CH₂)_(n2)—; n2 is an integerbetween 1 and 2,000; R⁴ is —R²—R^(3a)—, —R²—R^(3b)—, or —R^(3a)—R²—; R⁵is —R⁹—R⁶—R⁹—; R⁶ is —C(O)—NH—R^(3a)—; Y is —CH═CH—C(O)OR⁸,—CH═C(CH₃)—C(O)OR⁸, —COOR⁷, —N₃, —C≡C—R⁸, —NH₂, —CHO, —OH, -epoxide-R⁸,or —SH; with the proviso that when n is 0, Y is —CH═CH—C(O)OR⁸ or—CH═C(CH₃)—C(O)OR⁸; with the proviso that when R¹ is R^(3a) or—R²—R^(3a)—, Y is —CH═CH—C(O)OR⁸ or —CH═C(CH₃)—C(O)OR⁸; R⁷ is C₁₋₄alkyl, or a moiety such that —COOR⁷ is an activated ester; R⁸ ishydrogen or C₁₋₄ alkyl; and R⁹ is independently C₁₋₄ alkyl.
 2. Thecurcumin derivative according to claim 1, wherein: R² is a saturated orunsaturated, unbranched hydrocarbyl with 1 to 18 carbon atoms; n2 is aninteger between 1 and 50; R⁷ is C₁₋₂ alkyl, or a moiety such that —COOR⁷is an activated ester; R⁸ is hydrogen or C₁₋₂ alkyl; and R⁹ is C₁₋₂alkyl.
 3. The curcumin derivative according to claim 2, wherein: R² is asaturated, unbranched hydrocarbyl with 1 to 5 carbon atoms; and Y is—CH═CH—C(O)OR⁸, —CH═C(CH₃)—C(O)OR⁸, —COOR⁷, —N₃, or —C≡C—R⁸.
 4. Thecurcumin derivative according to claim 1, wherein the maximum value forn2 is
 12. 5. The curcumin derivative according to claim 1, wherein theactivated ester is an N-hydroxysuccinimide ester or a nitrophenyl ester.6. A curcumin derivative, selected from the group consisting of:

wherein n2 is an integer between 1 and 2,000, and wherein A is —CH₂—CH₂—or —CH═CH—.
 7. The curcumin derivative according to claim 1, wherein Yis —CH═CH—C(O)OR⁸ or —CH═C(CH₃)—C(O)OR⁸.
 8. The curcumin derivativeaccording to claim 1, wherein Y is —C≡C—R⁸.
 9. The curcumin derivativeaccording to claim 1, wherein Y is —N₃.
 10. The curcumin derivativeaccording to claim 1, wherein Y is NH₂.
 11. A curcumin derivative thatis curcumin acrylate, selected from the group consisting of:

wherein A is —CH₂—CH₂— or —CH═CH—.
 12. A curcumin derivative having theformula:

wherein A is —CH₂—CH₂— or —CH═CH—.
 13. A curcumin derivative having theformula I:Z-L_(n)-Y   (I) wherein: Z is represented by:

A is —CH₂—CH₂— or —CH═CH—; L is —[C(O)]_(n1)—R¹—; n is 0 or 1; n1 is 0or 1; R¹ is R², R^(3a), R⁴, or R⁵; R² is a saturated or unsaturated,branched or unbranched hydrocarbyl with 1 to 18 carbon atoms; R^(3a) is—(CH₂—CH₂—O)_(n2)—; R^(3b) is —(O—CH₂—CH₂)_(n2)—; n2 is an integerbetween 1 and 2,000; R⁴ is —R²—R^(3a)—, —R²—R^(3b)—, or —R^(3a)—R²—; R⁵is —R⁹—R⁶—R⁹—; R⁶ is —C(O)—NH—R^(3a)—; Y is —CH═CH—C(O)OR⁸,—CH═C(CH₃)—C(O)OR⁸, —N₃, —C≡C—R⁸, or —NH₂; with the proviso that when nis 0, Y is —CH═CH—C(O)OR⁸ or —CH═C(CH₃)—C(O)OR⁸; with the proviso thatwhen R¹ is R^(3a) or —R²—R^(3a)—, Y is —CH═CH—C(O)OR⁸ orCH═C(CH₃)—C(O)OR⁸; R⁸ is hydrogen or C₁₋₄ alkyl; and R⁹ is independentlyC₁₋₄ alkyl.
 14. A curcumin derivative having the formula I:Z-L_(n)-Y   (I) wherein: Z is represented by:

A is —CH₂—CH₂— or —CH═CH—; L is —[C(O)]_(n1)—R¹—; n is 0 or 1; n1 is 0or 1; R¹ is R², R^(3a), R⁴, or R⁵; R² is a saturated or unsaturated,branched or unbranched hydrocarbyl with 1 to 18 carbon atoms; R^(3a) is—(CH₂—CH₂—O)_(n2)—; R^(3b) is —(O—CH₂—CH₂)_(n2)—; n2 is an integerbetween 1 and 2,000; R⁴ is —R²—R^(3a)—, —R²—R^(3b)—, or —R^(3a)—R²—; R⁵is —R⁹—R⁶—R⁹—; R⁶ is —C(O)—NH—R^(3a)—; Y is —CHO, —OH, -epoxide-R⁸, or—SH; with the proviso that when n is 0, Y is —CH═CH—C(O)OR⁸ or—CH═C(CH₃)—C(O)OR⁸; with the proviso that when R¹ is R^(3a) or—R²—R^(3a)—, Y is —CH═CH—C(O)OR⁸ or CH═C(CH₃)—C(O)OR⁸; R⁸ is hydrogen orC₁₋₄ alkyl; and R⁹ is independently C₁₋₄ alkyl.